Nematodes are frequent infectious agents of both human and veterinary animal subjects. Filarial nematodes (belonging to the superfamily Filarioidea) are responsible for a global health burden of approximately 6.3 million disability-adjusted life-years, which represents the greatest single component of morbidity attributable to helminths affecting humans. No vaccine exists for the major filarial diseases, lymphatic filariasis and onchocerciasis; in part because research on protective immunity against filariae has been hampered by the inability of the human-parasitic species to complete their lifecycles in laboratory mice. However, the rodent filaria Litomosoides sigmodontis has become a popular experimental model over the past two decades, as BALB/c mice are fully permissive for its development and reproduction.
Lymphatic filariasis (LF) or “elephantiasis”, which is distributed across Africa, South Asia, the Pacific, Latin America and the Caribbean, accounts for 92% of this toll; while the remainder is caused by onchocerciasis or “river blindness”, primarily in sub-Saharan Africa. The major human filarial pathogens are Wuchereria bancrofti (which is responsible for 90% of LF cases), Brugia malayi and Brugia timori (geographically restricted causes of LF), and Onchocerca volvulus (the sole agent of human onchocerciasis). In addition, Loa loa affects ˜13 million people in West and Central Africa, generally causing a relatively mild disease, although infection has been associated with severe and sometimes fatal adverse events following chemotherapy. Filarial parasites are primarily drivers of chronic morbidity, which manifests as disabling swelling of the legs, genitals and breasts in LF; or visual impairment and severe dermatitis in onchocerciasis. Furthermore, filarial parasites are also a major problem in small animal veterinary medicine, with ˜0.5 million dogs in the USA alone infected with Dirofilaria immitis, the cause of potentially fatal heartworm disease.
Currently, control of human filarial diseases is almost entirely dependent on three anthelminthic drugs (ivermectin, diethylcarbamazine and albendazole), while prevention of heartworm also relies on prophylactic treatment of dogs and cats with ivermectin or other macrocyclic lactones. Reports of potential ivermectin resistance in O. volvulus and D. immitis have highlighted the importance of maintaining research efforts in vaccine development against filarial nematodes. However, rational vaccine design has been constrained for several decades by the intrinsic complexity of these metazoan parasites and their multistage lifecycle, which involves uptake of the first-stage larvae (microfilariae, Mf) by an haematophagous arthropod, two moults in the vector, transmission of third-stage larvae (L3) to a new vertebrate host, and two further moults before the worms mature as dioecious adults in a species-specific, parenteral predilection site. Moreover, the presence of obligate bacterial endosymbionts (Wolbachia) in many species of filarial nematodes adds another level of immunogenic stimuli to these pathogens, the impact of which remains incompletely defined. Following the publication of annotated genome sequences for B. malayi, D. immitis and L. loa, our understanding of the protein repertoire in filarial nematodes has been extended considerably by proteomic analyses of both whole body extracts (WBE) and excretory-secretory products (ESP), although only two studies (both of B. malayi) have examined stage-specific filarial secretomes to date. In the context of vaccine design, the identification of ESP proteins and determination of their expression in each major lifecycle stage can facilitate the prioritisation of candidates for efficacy screening in animal models.
One of the most popular rodent models for filarial research, which was first used during the 1940s in its natural host (the cotton rat, Sigmodon hispidus), is Litomosoides sigmodontis which was previously designated as L. carinii, though this nomenclature is taxonomically incorrect. The utility of this model for both basic immunological studies and vaccine screening changed radically with the discovery that unlike B. malayi and indeed all other filarial species, L. sigmodontis can complete its lifecycle in immunocompetent laboratory mice. Consequently, over the past two decades this model has drawn on the full power of murine immunology, including defined knockout strains, to address questions regarding the fundamental immunomodulatory mechanisms employed by filarial parasites, their susceptibility to different modes of vaccination, and most recently, their ability to mitigate proinflammatory pathology and autoimmune disease. In particular, the L. sigmodontis model has been central in defining the role of T-regulatory cells in filarial immune evasion, and has enabled the assessment of the impact of various vaccine strategies not only on adult worm burden, but on fecundity as determined by the density of Mf circulating in the bloodstream.